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Oxygen Sensing, Homeostasis, and Disease Semenza. NEJM , August 2011, 246: 6

Oxygen Sensing, Homeostasis, and Disease Semenza. NEJM , August 2011, 246: 6. Amelia Crawford PA-S2. Hypoxia Inducible Factor 1. All nucleated cells in the human body respond to hypoxia HIF-1 plays a critical role in the cells’ response.

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Oxygen Sensing, Homeostasis, and Disease Semenza. NEJM , August 2011, 246: 6

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  1. Oxygen Sensing, Homeostasis, and DiseaseSemenza.NEJM, August 2011, 246: 6 Amelia Crawford PA-S2

  2. Hypoxia Inducible Factor 1 • All nucleated cells in the human body respond to hypoxia • HIF-1 plays a critical role in the cells’ response. • When oxygen availability is decreased, HIF-1 regulates the expression of genes that mediate adaptive responses by cells

  3. Hypoxia Inducible Factor 1 • HIF-1 is composed of a beta and an alpha subunit. • The alpha subunit is oxygen regulated • In aerobic conditions, HLF-1 (alpha) is normally hydroxylated and then degraded by proteasomes • In hypoxic conditions, the hydroxylation is inhibited, HIF-1 (alpha) accumulates, and it up regulates several genes to promote survival in cells • Stimulates erythropoetin, angiogenesis, & glycolytic metabolism

  4. HIF-1

  5. HIF-1 and Cardiovascular Disease • Atherosclerotic disease causes stenosis of vessels and results in decreased blood flow distally. • Decreased blood flow →decreased O2 supply • In studies with mice in which the femoral artery was ligated, induction of HIF-1 resulted in increased activation of VEGF, which eventually caused angiogenesis and reperfusion of the limb via the production of collateral blood flow. • The normal adaptive vascular response is impaired by aging & DM—major causes of CAD and PVD

  6. HIF-1 and Cardiovascular Disease • VEGF other factors promote angiogenesis by stimulating vascular cells and also by mobilizing bone-marrow derived angiogenic cells (BMDACs) • BMDACs = myeloid cells that stimulate vascular remodeling. • In order to initiate a vascular response, they must mobilized from bone marrow, enter the peripheral blood, and be retained within the ischemic tissue by adhering to the vascular endothelium. • Aging results in the loss of ischemia induced expression of angiogenic factors and BMDAC mobilization and consequently, angiogenesis and reperfusion are decreased.

  7. HIF-1 and Cardiovascular Disease • HIF-1α induction occurs early in the course of a MI • In studies with mice with an over expression of HIF-1αthat underwent coronary artery ligation, there was a smaller infarct size, improved cardiac function, and increased capillary density. • Collateral vessels are routinely identified in 2/3 of patients with critical coronary artery disease that is sufficient to cause angina. • Patients with a collateral blood supply that eventually suffered a MI also had smaller infarcts and were more likely to survive than those without a collateral vessels. • HIF-1 also helps the heart to survive episodes of O2 deprivation by inducing glycolytic metabolism & adenosine production

  8. HIF-1 and Cardiovascular Disease • Pharmacologic agents that activate HIF-1 are a therapeutic target in treating patients with CAD and PVD (Gene therapy) • In preclinical trials, patients with CAD or PVD were given a recombinant adenovirus that encoded for a protein that contained the terminal half of HIF-1 alpha gene fused to an activator protein. • It was administered either via an IM injection (PVD) or intramyocardial injections (CAD) prior to CABG • No adverse effects were seen but also no reports of efficacy were released. This could be due to the fact that the protein did not contain all of the HIF-1 alpha gene and in turn did not encode for all the activities of the gene.

  9. HIF-1 and Cardiovascular Disease • Another pharmacologic alternative for targeting HIF-1 in cardiovascular disease is the development of drugs that inhibit the hydroxylation of HIF-1. • These drugs either: • 1. chelate Fe, (Fe is present in the center of the hydroxylases) or • 2. compete with the hydroxylases at the binding site

  10. HIF-1 and Cardiovascular Disease • A final alternative would be the use of HIF target gene products as therapeutic agents. • Already been done via cloning of erythropoietin gene and production of recombinant human erythropoietin. • Used in chronic renal failure patients to stimulate RBC production • However administration of a single angiogenic factor such as VEGF fails to stimulate a vascular response. • Benefit of using downstream proteins as therapeutic agents is that they act immediately whereas gene therapy requires more time for trascription and translation of target gene products.

  11. HIF-1 and Cancer • In cancer the physiologic responses to hypoxia aids in disease progression • Tumor vessels are structurally & functionally abnormal and contain areas of severe hypoxia. • This results in HIF-1 over expression, which causes additional angiogenesis, genetic instability, immune evasion, metabolic reprogramming, and invasion, and metastasis.

  12. HIF-1 and Cancer • Hypoxia within the tumor is a major mechanism that activates HIF-1 • Loss of tumor suppressor function or increased oncogene function also activates HIF-1. • HIF-1 regulates a myriad of target genes • However, only a small subset of genes in any given cancer will be regulated by HIF-1 • The role of HIF-1 in a specific cancer can guide possible therapies.

  13. HIF-1 and Cancer • A number of chemotherapy agents are directed at inhibiting HIF-1 • Topotecan • Also cardiac glycosides like Digoxin have been shown to decrease HIF-1 and subsequent tumor growth in mice. • Others are agents aimed at blocking HIF-1 are being investigated

  14. HIF-1 and Pulmonary Hypertension • Pulmonary hypertension is a progressive and often fatal consequence of chronic lung disease • In contrast to systemic arterioles which dilate in order to increase tissue perfusion during hypoxia, pulmonary arterioles constrict to shunt blood away from areas of the lung that are not ventilated • This eventually leads to corpulmonale and progressive hypoxemia.

  15. HIF-1 and Pulmonary Hypertension • HIFs regulate target genes that play major roles in the pathology of pulmonary HTN. • Alveolar hypoxia induces HIF-1 activity in vascular smooth muscle cells and alters the intracellular concentrations of K, Ca, & H ions • This leads to smooth muscle cell hypertrophy, proliferation, depolarization, & contraction and increased pulmonary vascular resistance

  16. HIF-1 and Pulmonary Hypertension • Tibetans live in conditions of chronic hypoxia & they have blunted responses to hypoxia, which prevents the development of pulmonary hypertension. • Gene sequencing has revealed loci encoding HIF-2α, hyroxylases (PHD2), factor inhibiting HIF-1, and HIF target genes as playing a significant role in the adaptation that Tibetans exhibit. • Alters vascular, erythropoeitic, and metabolic responses to hypoxia

  17. Conclusions • HIF-1 is an adaptive response in cardiovascular and peripheral vascular disease • HIF-1 is mal-adaptive in cancer • HIF-1 is also maladaptive in chronic lung disease and pulmonary hypertension. • The targeting of HIFs and its inhibitors and activators offer possible treatment options of these diseases.

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